Pancreatic ductal adenocarcinoma (PDAC) is a highly fatal disease with an overall 5-year survival of <5%. Progress in PDAC lags behind other cancers and there is a tremendous need to better understand the etiology of PDAC in order to develop early diagnostic methods and better treatments. Pancreatic carcinogenesis is driven by inflammation. Established risk factors for pancreatic cancer include chronic pancreatitis, diabetes, obesity, and smoking, each associated with an inflammatory mechanism. However, these risk factors do not fully explain the majority of pancreatic cancer cases. Emerging evidence suggests that variation in our `other genome'?the collective genome of the microorganisms inhabiting our body, known as the microbiome?may have an even greater role than the human genome variations in the pathogenesis of cancer. Recent discoveries suggest that bacteria are likely to influence this process by activating immune receptors and perpetuating cancer-associated inflammation. Further investigations are needed to fully understand the interaction between inflammation and the microbiota in the development of this deadly disease. We propose to characterize the microbiota in pancreatic tissue from patients with chronic pancreatitis, chronic pancreatitis and pancreaticogenic (T3cDM) diabetes mellitus, and PDAC using next-generation sequencing protocols. We will also characterize microbiota present in the pancreatic juice, saliva, and stools of the same subjects aiming to find correlative microbial signatures across multiple body sites. The Alkek Center for Metagenomics and Microbiome Research at Baylor College of Medicine (BCM) is a world leader in the study of the microbiome with innovative approaches and thus is ideally suited to coordinate this study. In addition, the Elkins Pancreas Center (EPC) at BCM is eminently suited to be a collaborative member of a national pancreatic research consortium. The EPC will provide access to a large population of patients with pancreatitis, T3cDM, and PDAC, and considerable experience in collaboration for the conduct of clinical trials, sophisticated prospective data collection, and access to a mature tissue repository for studies proposed by the Consortium. This project is timely and highly relevant to the goals of the NIH Roadmap and the NIH Human Microbiome Project. This novel approach will allow us to create a pathogenic model for pancreatic cancer that will offer innovative strategies for prevention, biomarkers for early detection, and targets for intervention.